Some harms of beta-carotene supplementation may persist after discontinuing use

November 30, 2004

A 6-year follow-up of a large, randomized trial in people with a history of smoking has found that the overall harm associated with beta-carotene supplementation on cardiovascular disease mortality disappeared quickly after participants stopped taking the supplements. However, the risk of lung cancer may persist, especially in females and former smokers, according to the study in the December 1 issue of the Journal of the National Cancer Institute.

In the 1980s, preliminary studies suggested that beta-carotene might have chemopreventive abilities, so two large, randomized trials were begun to test the supplement's effect on lung cancer among cigarette smokers: the Alpha-Tocopherol Beta-Carotene (ATBC) Trial, which was conducted in Finland, and the Beta-Carotene and Retinol Efficacy Trial (CARET), which was conducted in the United States. Both trials were stopped after evidence accumulated that the supplements were associated with an increased risk of lung cancer. In CARET, the group that received beta-carotene supplements had a 28% greater incidence of lung cancer and 17% more deaths from all causes compared with the placebo group.

To determine if the effects of beta-carotene supplementation continued after participants stopped taking the supplements, Gary E. Goodman, M.D., of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues followed the more than 18,000 participants in CARET for 6 years after the trial was stopped, until the end of 2001.

The increased risk of cardiovascular disease mortality quickly disappeared after participants stopped taking the supplements. However, women had a higher risk of death from cardiovascular disease or from any cause than men. In addition, the incidence of lung cancer and deaths from all causes decreased but did not disappear completely after the supplementation ceased. The excess risk of lung cancer was restricted primarily to females and former smokers.

"When chemoprevention agents are administered to large, healthy populations, it is necessary to document long-term safety, efficacy and, importantly, the duration of the beneficial (or adverse) effect," the authors write. "This is especially true when the basic underlying molecular and genetic mechanism of the agent is unclear. The results of CARET and ATBC emphasize that chemoprevention trials require careful monitoring of all disease endpoints ... even after the study intervention is discontinued."

In an editorial, Anna J. Duffield-Lillico, Ph.D., and Colin B. Begg, Ph.D., of Memorial Sloan-Kettering Cancer Center in New York, discuss these latest findings and their relation to other prevention trials using beta-carotene. In addition, they write, "These findings suggest that the adverse effects of high-dose beta-carotene on lung cancer incidence and overall mortality ... may be related to the pharmacologic doses of beta-carotene used and the resultant supra-physiologic serum concentrations of beta-carotene."
  • Article:
  • Editorial: Christine Hickey, Department of Public Affairs, Memorial Sloan-Kettering Cancer Center, 212-639-3627,

  • Article: Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens Jr. FL, Omenn GS, et al. The Beta-Carotene and Retinol Efficacy Trial: Incidence of Lung Cancer and Cardiovascular Disease Mortality During 6-Year Follow-up After Stopping Beta-Carotene and Retinol Supplements. J Natl Cancer Inst 2004;96:1743-50.
  • Editorial: Duffield-Lillico AJ, Begg CB. Reflections on the Landmark Studies of Beta-Carotene Supplementation. J Natl Cancer Inst 2004;96:1729-31.

    Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage. Visit the Journal online at

    Journal of the National Cancer Institute

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